The ultimate goals of schizophrenia research are to achieve understanding of the relationships between its genetic and environmental risk factors, biological and mental abnormalities, and pharmacological and psychosocial interventions effective in prevention/treatment of associated pathology. My career goal is to establish an effective, inter-disciplinary research program that will improve our understanding of schizophrenia throughout its multiple levels of pathology. The present project will be an important step toward this goal because it will take an inter-disciplinary approach to examine molecular genetic and neurocognitive bases of a core feature of schizophrenia - deficits in adaptive function. My doctoral training as a cognitive neuroscientist, followed by a post-doctoral fellowship in psychiatric neuroimaging and electrophysiology, have provided me with the necessary expertise to study neurocognitive phenotypes of schizophrenia. I now wish to integrate my training in neuropsychiatry with training in genetics that will enable me to investigate the association between specific genes and neurocognitive phenotypes of schizophrenia. Mass. General Hospital provides an ideal environment for this training as it unites a number of outstanding laboratories working in neuroscience, psychiatry, and genetics. Despite recent progress in understanding the molecular biology of the DLPFC, the neurocognitive mechanisms by which this system contributes to maladaptive behavior in schizophrenia are not yet well understood. Our preliminary data suggest that DLPFC mechanisms mediating specific real-world knowledge critical for flexible behavior are impaired in schizophrenia. The overall goal of this project is to examine contributions of COMT and MTHFR genes, known to influence prefrontal function, to these abnormalities. We will assay target neurocognitive mechanisms by recording high spatial resolution functional magnetic resonance imaging (fMRI) data and cost-effective electrophysiological (ERR) data while schizophrenia patients and healthy controls participate in a novel, ecologically valid paradigm that presents real-world goal- directed behaviors, conveyed in video clips. PUBLIC HEALTH RELEVANCE: This study may clarify the neurocognitive interpretation of the contributions of two candidate genes to the symptoms of schizophrenia. The results may direct future research of real-world knowledge acquisition in children at genetic risk for schizophrenia, with an ultimate goal to design early intervention treatments. They may help to develop a new endophenotype of schizophrenia to assist search for susceptibility genes of this disorder.